During the last several years a number of macroline-related indole alkaloids have been isolated from Alstonia macrophylla Wall, 1a-e Alstonia muelleriana Domin, 2a-f and other Alstonia species. As illustrated in Scheme I, the macroline bases consist of both monomeric and bisindale alkaloids, the complex structures of which have not fallen to total synthesis to date. Recently, the stereospecific formation of 1,3-disubstituted tetrahydro Beta-carbolines by the Pictet-Spengler reaction accompanied by complete transfer of chirality from the chiral amino acid ester of tryptophan to position-1 of the tetrahydro Beta-carboline has been developed in our laboratory in the Na-H, Nb-benzyl series, as well as the Na-CH3, NI series. This technology provides an extremely facile method to construct rings A,B,C, and D of the macroline alkaloids in optically active form. Ring E will then be added in stereospecific fashion via an intramolecular (3,3) sigmatropic rearrangement (an ester enolate Claisen rearrangement). It is proposed then to expand and exploit these methods to prepare the optically active macroline alkaloids, macroline 1, alstophylline 6, alstonisine 7, alstonerine 8, suaveoline 9, and to conclude this investigation by the total synthesis of the bisindole alkaloid, macralstonine 4 (C4-3H52N405). The synthesis of 4 is at a very exciting stage for the critical process of bond formation between the monomeric units of macroline 1 (drived from villastonine) and alstophylline (plant derived) has been carried out thus assuring success in this phase of the study. Philosophically, the approach is a general one capable of future extension to other Alstonia alkaloids including alkaloid H and macrosalhin. It has been suggested by LeQuesne that 1, or a suitable equivalent is the biosynthetic precursor for the macroline portion of the Alstonia bases. Intermediates related to 1 can later be labeled and employed to study the biogenesis of this family of alkaloids. Since 4 has been shown to potently lower blood pressure in dogs, the intermediates which occur late in the synthetic sequence and the target alkaloids will be screened for antihypertensive activity in SHR. Furthermore, Beta-carboline intermediates formed early in the route will be screened in vitro (benzodiazepine receptor) and in vivo (male mice, later rats) in regard to their abilities to antagonize the effects of diazepan, decrease sleep time in animals and to reverse the effects of benzodiazepine-alcohol or barbituate induced CNS depression in laboratory rats. In fact, 3-hydroxymethyl Beta-carboline and related Beta-carbolines have been shown to do just this.